The retinoids are a class of chemical compounds that are structurally related to vitamin A. Retinoid compounds have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes. Retinoid compounds are also being researched as treatments for skin cancer. For example, 9-cis-retinoic acid is used topically to help treat skin lesions from Kaposi's sarcoma.
Retinoid compounds consist of four isoprenoid units joined in a head-to-tail manner. The basic structure of a retinoid compound includes a cyclic end group, a polyene side chain and a polar end group. The conjugation (i.e. alternating single and double bonds) of the polyene side chain is responsible for the color of retinoid compounds (typically yellow, orange, or red) and their ability to act as chromophores. Variations in the side chain and polar end group of these compounds lead to different classes of retinoid compounds.
Retinoid compounds are classified into three generations. First and second generation retinoid compounds are capable of binding to several retinoid receptors due to the flexibility imparted by their polyene side chain. Third generation retinoid compounds are less flexible than the first and second generation retinoid compounds and interact with fewer retinoid receptors. Examples of retinoid compounds are shown in Table 1.
TABLE 1Examples of Retinoid CompoundsFirst GenerationRetinol Retinal All-trans-Retinoic Acid (Tretinoin, Retin-A) 13-cis-Retinoic Acid (Isotretinoin) 9-cis-Retinoic Acid (Alitretinoin) Second GenerationEtretinate Acitretin Third GenerationBexarotene Tazarotene Adapalene
Isotretinoin (13-cis-retinoic acid) is a retinoid compound with anti-inflammatory and anti-tumor action. This action is mediated through the beta and alpha retinoic acid receptors (RAR-β, RAR-α). Isotretinoin attenuates iNOS expression and activity in cytokine-stimulated murine mesangial cells. It induces mitochondrial membrane permeability transition, observed as swelling and as a decrease in membrane potential, and stimulates the release of cytochrome c implicating mechanisms through the apoptosis pathway. These activities are reversed by EGTA and cyclosporine A. Isotretinoin also increases MMP-1 protein expression partially via increased transcription. Isotretinoin is used in oral and topical anti-acne medications and in topical medications that are used to treat sun-damaged skin.
Retinol is an endogenous retinoid compound that helps in vision, bone growth, reproduction, growth of epithelium cells, and fighting infections. Once retinol has been taken up by a cell, it can be oxidized to retinal, which is further oxidized to retinoic acid. Retinoic acid acts as a ligand for both the RAR and the retinoid X receptor (RXR). Retinol appears to function in maintaining normal skin health and is often used in high price consumer products for treating aged and wrinkled skin.
Tretinoin has been shown to both treat acne and reverse some of the changes in the skin due to photo-aging, i.e. sun damage. If used long term, tretinoin may reduce some fine wrinkles, freckles, comedones (whiteheads and blackheads), and solar keratoses (dry scaly sun-spots). With prolonged use, tretinoin protects the skin against harmful UVB and UVA rays (Bhawan et al., 1996).
When using topical retinoid compounds, patients should be advised to incorporate preventative, healthy practices with respect to exposure to the sun. Damaging rays from the sun can penetrate the clouds and even glass. Therefore, people working by a window or riding in a vehicle also risk exposure to damaging rays. Sunscreens are considered the gold standard for protecting the skin from the harmful effects of UV light (Leyden, 2003), and a broad spectrum (UVB/UVA) sunscreen with key ingredients such as Avobenzone provides the most protection. Sunscreen should be applied daily, even on cloudy days and during the winter months. Patients should protect exposed areas of the skin with an appropriate sunscreen 30 minutes prior to exposure, followed by a second application to ensure adequate coverage. Often, once-a-day sunscreen application is not enough and sunscreen should be reapplied throughout the day. When exposed to the elements, sunscreen application is recommended to be applied every 2 hours and more often if sweating or swimming. When feasible, peak hours of the sun should be avoided (10 am to 4 pm), and patients should seek shade when they can. A sun-protection lip balm is also beneficial. If prolonged sun exposure is expected, such as during a vacation, the use of the topical retinoid compound should be discontinued one week before the exposure and resumed upon return.
One major drawback to the clinical use of retinoid compounds, especially topically as anti-acne, anti-aging, and wrinkle-reducing applications described herein, is the high reactivity of the conjugated polyene tail towards light. The absorption of ultraviolet light by a chromophore-containing organic molecule causes the excitation of an electron in the chromophore moiety from an initially occupied, low energy orbital to a higher energy, previously unoccupied orbital. The energy of the absorbed photon is used to energize an electron and cause it to “jump” to a higher energy orbital, see Turro, Modern Molecular Photochemistry, 1991. Two excited electronic states derive from the electronic orbital configuration produced by UV light absorption. In one state, the electron spins are paired (antiparallel) and in the other state the electron spins are unpaired (parallel). The state with paired spins has no resultant spin magnetic moment, but the state with unpaired spins possesses a net spin magnetic moment. A state with paired spins remains a single state in the presence of a magnetic field, and is termed a singlet state. A state with unpaired spins interacts with a magnetic field and splits into three quantized states, and is termed a triplet state.
In the electronically excited state, the chromophore-containing organic molecule is prone to degrade via a number of known pathways and, therefore, can absorb little or no additional UV light. To photostabilize an electronically excited chromophore-containing organic molecule in order to provide sufficient UV protection, it must be returned to the ground state before it undergoes a photochemical reaction destructive to its UV absorbing capability. There are known photostabilizing sunscreen additives, such as octocrylene, methylbenzilydene camphor, and the esters or polyesters of naphthalene dicarboxylic acid of this assignee's U.S. Pat. Nos. 6,113,931; 6,284,916; 6,518,451; and 6,551,605, all hereby incorporated by reference, that are capable of quenching excited triplet state energy. As shown in this assignee's pending application Ser. Nos. 11/891,281 and 12/022,758 filed on Aug. 9, 2007 and Jan. 30, 2008, respectively, the disclosure of which are hereby incorporated by reference, it has also been found that alkoxycrylenes, particularly methoxycrylenes, return chromophore-containing organic molecules, particularly butyl methoxydibenzoylmethane (Avobenzone), octyl methoxycinnamate (Octinoxate), and octyl salicylate (Octisalate), from both an electronically excited singlet state and excited triplet state back to their ground state, thereby photostabilizing the UV-absorbing organic molecules.
When retinoid compounds are exposed to light, they also undergo photodegradation via a number of pathways, including undesirable isomerization reactions, photoaddition/substitution reactions, and cycloadditions, all of which destroy the integrity of the retinoid and its ability to function as intended. For example, isotretinoin normally absorbs ultraviolet radiation strongly (ε=44,000) with a peak at 366 nm (FIG. 1). After isotretinoin is exposed to 5 MED (105 mJ/cm2) of UV radiation, which is equal to about one hour's worth of exposure to sunlight, the amount of isotretinoin decreases significantly (FIG. 2).
This photoinstability of retinoid compounds is highly problematic when developing and using topical retinoid compounds and retinoid compound-containing compositions for clinical purposes. To reduce the amount of photodegradation that occurs in topical retinoid compound-containing products, manufacture of the retinoid product must occur in the dark or under special lighting conditions, and the packaging of the retinoid product must be light fast. Even if retinoid compound-containing products are manufactured in the dark and stored in a light fast package, they quickly degrade upon application to the skin, rendering the retinoid product ineffective.